Cupric nitrate catalyzed efficient and facile synthesis of 1,8-dioxo-octahydroxanthene derivatives

Article abstract of DOI:10.14233/ajchem.2013.15076

An efficient and convenient approach to the synthesis of 1,8-dioxo-octahydroxanthene derivatives by using catalytic amount (10 mol %) of cupric nitrate [Cu(NO₃)₂·3H₂O] in acetonitrile and the yields obtained are in good to

Full text of DOI:10.14233/ajchem.2013.15076

Asian Journal of Chemistry; Vol. 25, No. 13 (2013), 7535-7538
http://dx.doi.org/10.14233/ajchem.2013.15076
Cupric Nitrate Catalyzed Efficient and Facile Synthesis of
1,8-Dioxo-octahydroxanthene Derivatives
AAYESHA NASREEN
Department of Chemistry, College of Sciences, Jazan University, 6811-Arroudah, Jazan 82724-3750, P.O. Box No. 2097, Kingdom of Saudi Arabia
Corresponding author: Fax: +966 073227066; E-mail: aayesha_iict@yahoo.co.in
(
Received: 31 December 2012;
Accepted: 1 July 2013)
AJC-13745
An efficient and convenient approach to the synthesis of 1,8-dioxo-octahydroxanthene derivatives by using catalytic amount (10 mol %)
of cupric nitrate [Cu(NO ·3H O] in acetonitrile and the yields obtained are in good to excellent (75-96 %). The reaction is highly chemo
selective and applicable to aldehydes only.
3
)
2
2
Key Words: 1,8-Dioxo-octahydroxanthene Derivatives, Acetonitrile, Cupric nitrate, Aldehydes.
2
3
24
3
ammonium chloride , p-dodecyl benzenesulfonic acid , InCl /
INTRODUCTION
25
3+
26
ionic liquid and Fe -mont , have been reported for the syn-
thesis of xanthenedione derivatives. In which some of them
often involves the use of expensive reagents, hazard organic
solvents and tedious workup.
Xanthene derivatives have attracted considerable interest
in recent years because of their promising activity as positive
1
allosteric modulators of metabotropic (mGlu) receptors and
potent nonpeptidic inhibitors of recombinant human calpain
2
I . These have been used as rigid carbon skeletons for the
However, due to their great importance, there still needs
to be development of novel methods for the preparation of
xanthenediones. With the increasing environmental concerns
and the regulatory constraints faced in the chemical and pharma-
ceutical industries, development of environmentally friendly
benign organic reactions has become a crucial and demanding
construction of new chiral bidentate phosphine ligands with
3
potential applications in catalytic processes . In particular,
xanthenediones constitute a structural unit in a number of
4
natural products and have been used as versatile synthons
5
because of the inherent reactivity of the inbuilt pyran ring as
27
research area in modern organic chemical research . In
28
continuation of our interest in the area of clean synthesis
well as synthetic derivatives and occupy a prominent position
6
in medicinal chemistry .
herein, the synthesis of xanthenediones catalyzed by cupric
nitrate in acetonitrile is reported (Scheme-I).
The synthesis of xanthenediones usually condenses
appropriate active methylene carbonyl compounds with
7
aldehydes catalyzed by sulfuric acid or hydrochloric acid .
8
Vranken et al. described two-step synthesis of 9-aryl-6-
O
O
O
O
Ar
Ar
O
Cu(NO
CH
3
)
2
CN
.3H
2
O,
3
ArCHO
+
hydroxy-3H-xanthen-3-one fluorophores by condensation of
9
aryl aldehydes and fluororesorcinol. Singh et al. reported a
Reflux
O
O
OH OH
3
Intermediate)
(75-96%)
4a-4q)
4
new method for the preparation of xanthenediones through
carbon transfer reactions of 1,3-oxazinanes and oxazolidines
with carbon nucleophiles.
1
2
(
(
Scheme-I: Synthesis of 1,8-dioxo-octahydroxanthenes catalyzed by
Cu(NO ) ·3H O in acetonitrile
2
3
2
According to the availability and the economic viability
of starting materials, various catalysts such as tetra butyl am-
EXPERIMENTAL
10
monium hexatungstate [TBA] [W
2
6
O
19] , tetrabutyl ammonium
11
12
hydrogen sulphate , samarium chloride , calcium chloride
Chemicals were purchased from Fluka and S.D. Fine
chemicals and directly used for the synthesis. Thin layer
chromatography (TLC): precoated silica gel plates (60 F254,
1
3
14
in water , MontK10 , β-cyclodextrin ,
15
16
in DMSO , H
2
SO
4
1
7
18
DOWEX-50W , amino alcohol , saccharin sulphonic acid ,
19
20
1
diethyl ethoxymethylene malonate , Silica supported sodium
0.2 mm layer; E. Merck). H NMR (Avance 300 MHz) spectra
were recorded in CDCl using TMS as internal standard.
21
22
hydrogen sulphate , N-bromosuccinimide , benzyltriethyl
3

7
536 Nasreen
Asian J. Chem.
Chemical shifts (δ) are reported in ppm, Melting points (m.p.)
were determined on a Fischer-Johns melting point apparatus.
IR and MS were recorded on a Thermo Nicolet Nexus 670
FT-IR Spectrometer and Finnegan MAT 1020 Mass spectro-
meter operating at 70 eV.
TABLE-1
SCREENING OF VARIOUS METAL NITRATES
FOR THE MODEL REACTION
Entry
Catalyst
Yield (%)
1
2
3
4
5
6
7
8
9
Zn(NO ) ·6H O
3
50
NR
76
2
2
AgNO3
Fe(NO ) ·9H O
General procedure: To the stirred solution of
3
3
2
Cu(NO
,5-dimethyl-1,3-cyclohexanedione (dimedone) (2 mM) and
benzaldehyde (1 mM) and refluxed for the time specified in
Table-3). After completion of the reaction as indicated by
TLC, the reaction mixture was washed with water and extracted
into ether dried over anhydrous Na SO and concentrated under
3 2 2
) ·3H O in acetonitrile (5 mL) were added successively
Rh(NO ) ·2H O
3
65
3
2
5
La(NO ) ·6H O
3
70
3
2
Nd(NO )
3 3
2
·6H O
85
Cu(NO ) ·3H O
3
96
2
2
(
Ce(NH ) ·(NO )
3 6
40
4
2
Ni(NO ) ·6H O
3
NR
NR
45
3
2
2
4
10
Bi(NO ) ·5H O
3 3 2
vacuum, the obtained crude product was further purified by
column chromatography using EtOAc/hexane (1:9) to afford
the white solid of 3,3,6,6-tetramethyl-9-benzene-1,8-dioxo-
octahydroxanthene is obtained in 96 % yield. All the comp-
ounds are known and gave satisfactory spectroscopic data in
11
Al(NO ) ·9H O
3 3 2
a
Isolated yields, NR = No reaction.
TABLE-2
SCREENING OF VARIOUS SOLVENTS
FOR THE MODEL REACTION
11,21-26
accordance to the reported data
.
a
Entry
Solvent
DCM
DMF
THF
Yield (%)
NR
75
RESULTS AND DISCUSSION
1
2
3
4
5
6
7
8
9
In continuation of our interest in the development of
a highly expedient methodology for the synthesis of fine
chemicals like xanthenediones, which constitutes a structural
unit in natural products and used as synthons because of the
inbuilt pyran ring, we report here for the first time synthesis
of 1,8 di-oxo-octahydroxanthene derivatives 4 from the
conjugate addition of various aldehydes 1 and dimedone
30
H O
2
NR
96
3
CH CN
EtOAc
CHCl3
DEA
54
50
NR
50
Ethanol
a
Isolated yields, NR = No reaction.
(
5,5-dimethyl1,3-cyclohexanedione) 2 in the presence of
Cu(NO ·3H O in acetonitrile at reflux, as an efficient catalyst
Scheme-I).
Initially we have studied the efficacy of several metal
3
)
2
2
unsuccessful. To study their behaviour under the optimized
reaction parameters i.e., 10 mol % of Cu(NO ·3H O in aceto-
nitrile at reflux and summarizes the observations.
(
3
)
2
2
nitrates chosen (10 mol % as standard) for the model reaction
using dimedone (2 mmol) and benzaldehyde (1 mmol) in
acetonitrile (5 mL) being refluxed for 7 h to afford the corres-
ponding 3,3,6,6-tetramethyl-9-aryl1,8-dioxo-octahydro-
xanthene derivatives and the results are presented in (Table-1).
While comparing the effect of catalysts, we found that
The nature of substituent's on aromatic ring showed some
effect on this conversion. In general, electron rich counter parts
such as hydroxy group, methoxy group, methyl group and so
forth required less reaction times, than those of electron with-
drawing groups such as (nitro group, halide) were employed
and reacted well to give the corresponding, 1,8-dioxo-octahydro-
xanthene derivatives in good to excellent yields, without
undergoing polymerization and isomerisation. There were
Cu(NO
in terms of isolated yield (96 %) (Table-1, Entry 7). We choose
Cu(NO ·3H O as the suitable catalyst for further reactions
3 2 2
) ·3H O was more effective than other nitrates tested,
3
)
2
2
3 2 2
some limitations for the Cu(NO ) ·3H O catalyzed reaction,
due to its easy availability, cost effectiveness, easy handling,
intrigued by these observations, we have then tested the
surprisingly reaction with aliphatic aldehyde does not yield
the desired product, instead which gives some by products.
The possible mechanism to account for the reaction is
Knoevenagel addition between aldehyde and dimedone and
subsequently, water elimination of intermediate 3 (Scheme-
efficacy of several copper salts available such as Cu(OAc)
O, Cu(Cl, Br, I) along with Cu(NO ·3H O for the model
2
reaction and among the copper salts screened Cu(NO ·3H O
2
,
H
2
3
)
2
2
3
)
2
was found to be the best both in terms of reaction time and
yields.
2
6
I) resulted in the formation of desired product . Hetero-
aromatic aldehyde such as pyridine-2-carboxaldehyde survived
well without the formation of any side product under the
present reaction conditions giving the corresponding 1,8-
dioxo-octahydroxanthene derivatives in moderate yields. All
the products were well characterized (Table-3).
To examine the influence of effect of various solvents for
the model reaction, we also carried out the model reaction in
different organic solvents results are shown in (Table-2) and
among screened, acetonitrile (96 %) (Entry 5) was found to
be the best choice of solvent.An optimum amount of 10 mol %
The efficiency and generality of the present cupric nitrate
catalyzed protocol can be realized by comparing our result
for the reaction of benzaldehyde with dimedone chosen as
model substrate with those of some recently developed proce-
dures by comparing with respect to the reaction times-mol %
of the catalyst used and the yields. As it is evident from the
previous data, our protocol is comparatively better in terms of
3 2 2
of Cu(NO ) ·3H O in acetonitrile is sufficient to carry forward
the reaction. In the presence of catalyst at room temperature
for 24 h did not yield the product. Encouraged by these results
obtained for benzaldehyde we generalized the reaction scope
for a number of other structurally divergent aromatic aldehyde
and ketones. The reaction with aliphatic and aromatic ketones
such as cyclohexanone and acetophenone were found to be

Vol. 25, No. 13 (2013)
Efficient and Facile Synthesis of 1,8-Dioxo-octahydroxanthene Derivatives 7537
TABLE-3
SYNTHESIS OF 1,8-DIOXO-OCTAHYDROXANTHENES* CATALYZED BY Cu(NO ) ·3H O IN ACETONITRILE
3
2
2
m.p. (ºC)
Entry
Aldehyde
C H
τ (h)
Product
Yield (%)
Ref.
(
Found)
(Reported)
b
1
2
3
4
5
6
7
8
9
7.0
9.0
7.0
7.0
7.0
7.0
7.0
8.5
9.5
9.5
7.0
9.0
9.0
9.0
8.0
7.0
7.0
4a
4b
4c
4d
4e
4f
96
89
88
93
81
90
90
94
91
90
90
90
75
80
80
82
86
203-204
228-231
245-247
203-205
224-226
228-229
176
204-205
230-231
246-247
205-206
225-227
226-228
175-177
224-226
171-172
222
11
6
5
b
4-ClC H
6
11
4
b
4-HOC H
6
11
4
2-HOC H
6
18
26
26
4
3-HOC H
6
4
4-HO-3-CH OC H
3
3
6
b
C H CH=CH
6
4g
4h
4i
11
5
b
2-ClC H
6
227
11
4
b
3-NO C H
4
169-170
221-222
218-219
233
11
2
6
b
11
10
11
12
13
14
15
16
17
4-NO C H
4
4j
2
6
b
4-CH C H
4
4k
4l
217-218
234-236
224-226
188-190
183-184
242-245
190-191
11
3
6
4-BrC H
6
18
18
4
4-FC H
6
4m
4n
4o
4p
4q
225
4
b
2-C H N
5
187-189
182-183
244-245
186-188
11
4
b
11
3-ClC H
6
4
4-CH OC H
4
18
18
3
6
2-CH OC H
4
3
6
1
*
All the products are characterized by H NMR, mass and IR spectral analysis.
ready availability, easy handling, cost effectiveness and
remarkably low toxicity with most of the recently reported
catalysts.
Conclusion
A practical and new procedure is developed for the
synthesis of 1,8-dioxo-octahydroxanthene derivatives using
3 2 2
Cu(NO ) ·3H O as catalyst. The present protocol has several
Spectral data for selected compounds
advantages, mild reaction conditions, readily available, inex-
pensive catalyst, easy handling, excellent yields, greater
selectivity, operational and experimental simplicity. Study of
wide range of structurally divergent aldehydes we believe that,
Cu(NO ) ·3H O catalyzed methodology will definitely be a
3
,3,6,6-Tetramethyl-9-benzene-1,8-dioxo-octa-
-1
hydroxanthene (4a): IR (KBr, νmax, cm ): 3154, 1668, 1356,
1
1
274, 1201, 1198, 1138, 867. H NMR (300 MHz, CDCl
ppm): 0.98 (s, 6H, 2CH ), 1.12 (s, 6H, 2CH ) 2.20 (dd, 4H,
CH ), 2.43 (s, 4H, 2CH ), 4.70 (s, 1H, CH), 6.74 (m, 2H,
ArH), 6.95(m,3H, ArH); EI MS (m/z): 350 (M ).
,3,6,6-Tetramethyl-9-(4-chlorophenyl)-1,8-dioxo-
3
δ
3
3
3
2
2
2
2
2
valuable addition to the existing process in the field of synthesis
of 1,8-dioxo-octahydroxanthene derivatives.
+
3
-1
ACKNOWLEDGEMENTS
octahydroxanthene (4b): IR (KBr, νmax, cm ): 3086, 2989,
1
1
2
4
689, 1664, 1640, 1617, 1497, 1366, 1194, 1142, 1121, 1094,
The author thanks Head, Department of Chemistry Dr.
Rita for her cooperation and Jazan University, for giving an
opportunity to continue the research work.
1
021, 846. H NMR (CDCl
CH3), 1.01 (s, 6H, 2CH ), 2.19 (dd, 4H, 2CH
H, 2CH ), 4.72 (s, 1H, CH), 7.52-8.10 (m, 4H, ArH); EI MS
3
, 300 MHz, δ ppm) : 0.88 (s, 6H,
3
2
), 2.51 (dd,
2
(
m/z): 385 (M + 1).
,3,6,6-Tetramethyl-9-(4-nitrophenyl)-1,8-dioxo-
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